T160‐phosphorylated CDK2 defines threshold for HGF‐dependent proliferation in primary hepatocytes

Liver regeneration is a tightly controlled process mainly achieved by proliferation of usually quiescent hepatocytes. The specific molecular mechanisms ensuring cell division only in response to proliferative signals such as hepatocyte growth factor (HGF) are not fully understood. Here, we combined quantitative time-resolved analysis of primary mouse hepatocyte proliferation at the single cell and at the population level with mathematical modeling. We showed that numerous G1/S transition components are activated upon hepatocyte isolation whereas DNA replication only occurs upon additional HGF stimulation. In response to HGF, Cyclin:CDK complex formation was increased, p21 rather than p27 was regulated, and Rb expression was enhanced. Quantification of protein levels at the restriction point showed an excess of CDK2 over CDK4 and limiting amounts of the transcription factor E2F-1. Analysis with our mathematical model revealed that T160 phosphorylation of CDK2 correlated best with growth factor-dependent proliferation, which we validated experimentally on both the population and the single cell level. In conclusion, we identified CDK2 phosphorylation as a gate-keeping mechanism to maintain hepatocyte quiescence in the absence of HGF

Piecewise Linear Models for the Quasiperiodic Transition to Chaos

We formulate and study analytically and computationally two families of piecewise linear degree one circle maps. These families offer the rare advantage of being non-trivial but essentially solvable models for the phenomenon of mode-locking and the quasi-periodic transition to chaos. For instance, for these families, we obtain complete solutions to several questions still largely unanswered for families of smooth circle maps. Our main results describe (1) the sets of maps in these families having some prescribed rotation interval; (2) the boundaries between zero and positive topological entropy and between zero length and non-zero length rotation interval; and (3) the structure and bifurcations of the attractors in one of these families. We discuss the interpretation of these maps as low-order spline approximations to the classic ``sine-circle'' map and examine more generally the implications of our results for the case of smooth circle maps. We also mention a possible connection to recent experiments on models of a driven Josephson junction.Comment: 75 pages, plain TeX, 47 figures (available on request

First Results for the Beam Commissioning of the CERN Multi-Turn Extraction

The Multi-Turn Extraction (MTE), a new type of extraction based on beam trapping inside stable islands in horizontal phase space, has been commissioned during the 2008 run of the CERN Proton Synchrotron. Both singleand multi-bunch beams with a total intensity up to 1.4 1013 protons have been extracted with efficiencies up to 98%. Furthermore, injection tests in the CERN Super Proton Synchrotron were performed, with the beam then accelerated and extracted to produce neutrinos for the CERN Neutrino-to-Gran Sasso experiments. The results of the extensive measurement campaign are presented and discussed in detail

Ions for LHC: Towards Completion of the Injector Chain

The commissioning of CERN's ion injector complex [1] to allow 1.1 PeV collisions of ions in LHC is well under way. After the Low Energy Ion Ring (LEIR) in 2005 [2] and the Proton Synchrotron (PS) in 2006 [3], the Super Proton Synchrotron (SPS) has now been commissioned with the 'Early' ion beam, which should give a luminosity of $5×10^{25}cm^{-2}s^{-1}$ in the LHC. This paper summarizes the operation in 2007 of all the machines involved in the ion injection chain

The effect of acute vs chronic magnesium supplementation on exercise and recovery on resistance exercise, blood pressure and total peripheral resistance on normotensive adults

© 2015 Kass and Poeira; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Magnesium supplementation has previously shown reductions in blood pressure of up to 12 mmHg. A positive relationship between magnesium supplementation and performance gains in resistance exercise has also been seen. However, no previous studies have investigated loading strategies to optimise response. The aim of this study was to assess the effect of oral magnesium supplementation on resistance exercise and vascular response after intense exercise for an acute and chronic loading strategy on a 2-day repeat protocol. Methods: The study was a randomised, double-blind, cross-over design, placebo controlled 2 day repeat measure protocol (n = 13). Intense exercise (40 km time trial) was followed by bench press at 80% 1RM to exhaustion, with blood pressure and total peripheral resistance (TPR) recorded. 300 mg/d elemental magnesium was supplemented for either a 1 (A) or 4 (Chr) week loading strategy. Food diaries were recorded. Results: Dietary magnesium intake was above the Reference Nutrient Intake (RNI) for all groups. Bench press showed a significant increase of 17.7% (p = 0.031) for A on day 1. On day 2 A showed no decrease in performance whilst Chr showed a 32.1% decrease. On day 2 post-exercise systolic blood pressure (SBP) was significantly lower in both A (p = 0.0.47) and Chr (p = 0.016) groups. Diastolic blood pressure (DBP) showed significant decreases on day 2 solely for A (p = 0.047) with no changes in the Chr. TPR reduced for A on days 1 and 2 (p = 0.031) with Chr showing an increase on day 1 (p = 0.008) and no change on day 2. Conclusion: There was no cumulative effect of Chr supplementation compared to A. A group showed improvement for bench press concurring with previous research which was not seen in Chr. On day 2 A showed a small non-significant increase but not a decrement as expected with Chr showing a decrease. DBP showed reductions in both Chr and A loading, agreeing with previous literature. This is suggestive of a different mechanism for BP reduction than for muscular strength. TPR showed greater reductions with A than Chr, which would not be expected as both interventions had reductions in BP, which is associated with TPR.Peer reviewedFinal Published versio

Turkey research, 1966

The Ohio poultry industry / R. E. Cook -- Lighting turkeys for maximum reproductive performance / K. I. Brown -- Feeding the breeder turkey / S. P. Touchburn -- A comparison of methods for artificially inseminating turkeys / K. e. Nestor and K. I. Brown -- Broody management and egg production of turkeys / P. A. Renner and K. E. Nestor -- Egg quality and hatchability in turkeys / K. E. Nestor -- Importance of female sex hormones in the reproductive performance of turkey hens / D. P. Bajpayee and K. I. Brown -- Some factors affecting storage of turkey semen / K. I. Brown -- Feeding schedules for growing turkeys / S. P. Touchburn and V. D. Chamberlain -- Determining selling age of turkeys by returns over feed costs / R. L. Baker -- Effects of age of turkeys on the flavor of turkey meat / G. J. Mountney -- Early poult mortality / K. E. Nestor and P. A. Renner -- Airsacculitis in turkeys / Y. S. Mohamed and E. H. Bohl -- Some observations on wing notching of turkeys / V. D. Chamberlain -- Turkeys selected for resistance to stress / K. I. Brown -- Genetics of growth and reproduction / K. E. Nesto

Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma

The introduction of new drugs in the past years has substantially improved outcome in multiple myeloma (MM). However, the majority of patients eventually relapse and become resistant to one or multiple drugs. While the genetic landscape of relapsed/ resistant multiple myeloma has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated. To determine the functional impact of gene mutations, we performed combined whole-exome sequencing (WES) of longitudinal patient samples with CRISPR-Cas9 drug resistance screens for lenalidomide, bortezomib, dexamethasone, and melphalan. WES of longitudinal samples from 16 MM patients identified a large number of mutations in each patient that were newly acquired or evolved from a small subclone (median 9, range 1-55), including recurrent mutations in TP53, DNAH5, and WSCD2. Focused CRISPR-Cas9 resistance screens against 170 relapse-specific mutations functionally linked 15 of them to drug resistance. These included cereblon E3 ligase complex members for lenalidomide, structural genes PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. In contrast, inactivation of genes involved in the DNA damage repair pathway, including ATM, FANCA, RAD54B, and BRCC3, enhanced susceptibility to cytotoxic chemotherapy. Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future